Coagulation Disorders Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mr Daniel Wright, 22 years old, university student. ^[1]

Presenting complaint: Woke this morning with severe pain and swelling in his right knee, which developed spontaneously overnight. He also noticed a new large bruise on his right thigh. He feels a moderate headache but denies head injury, visual change, vomiting or focal weakness. ^[1]

Past history: Severe haemophilia A (factor VIII less than 1 IU/dL), diagnosed at 6 months of age after prolonged bleeding from a heel-prick. Recurrent haemarthroses since childhood — both knees, left ankle, right elbow — with evidence of early chronic arthropathy in both knees. Hospitalised at age 15 for an iliopsoas bleed. Hepatitis C antibody positive (acquired from contaminated factor concentrate in early childhood, genotype 1, treated with direct-acting antivirals at age 19 — sustained virological response confirmed). No history of HIV. No inhibitor history (Bethesda assay negative on last testing). ^[1]

Current management: Emicizumab 3 mg per kilogram subcutaneously every two weeks (started at age 20). Since starting emicizumab, his annualised bleed rate has fallen from 12 to 1. His last bleed was 4 months ago — a minor ankle haemarthrosis that resolved with a single dose of recombinant factor VIII. ^[1]

Family history: Mother is a carrier (factor VIII 0.45 IU/mL, asymptomatic). Maternal uncle with severe haemophilia A, died of intracranial haemorrhage at age 35. No siblings. ^[1]

Social history: Lives with his girlfriend. Third-year engineering student. Does not smoke, drinks alcohol occasionally. Keen on swimming (recommended low-impact sport). ^[1]

Examination findings (trainee elicits):

• Well-developed young man, in pain from the right knee.
• Right knee: swollen, warm, tender, held in 30 degrees of flexion, range of movement severely limited by pain.
• Left knee: signs of chronic arthropathy — bony enlargement, crepitus, reduced flexion to 100 degrees, wasting of the quadriceps.
• Right elbow: mild chronic arthropathy with reduced extension.
• Large ecchymosis on the right thigh (approximately 15 cm), non-tense.
• Neurological examination: GCS 15, no focal deficits. The headache is present but there is no neck stiffness, photophobia, papilloedema or focal signs. Cranial nerves intact.
• Cardiovascular, respiratory and abdominal examinations normal. ^[1]

Investigations:

• FBC: Hb 138 g/L, platelets 250 x 10^9/L, WCC 7.2.
• PT 12 seconds (normal), aPTT 62 seconds (prolonged — expected in haemophilia A and while on emicizumab).
• Factor VIII: less than 1 IU/dL (severe range, expected).
• Bethesda assay: negative (no inhibitor). ^[1]

Candidate's structured presentation (model)

Opening statement (SASPOP): ^[1]

"Mr Wright is a 22-year-old engineering student with severe haemophilia A who presents with a spontaneous right knee haemarthrosis and a large thigh bruise, on a background of emicizumab prophylaxis that has reduced his bleeding rate from 12 to 1 per year. He also reports a moderate headache without focal neurology — a red flag in haemophilia that I must address immediately." ^[1]

"His main problems are:

1. Acute right knee haemarthrosis — a breakthrough bleed despite emicizumab
2. Moderate headache in a severe haemophilia patient — must exclude intracranial haemorrhage
3. Large right thigh bruise — possible early muscle bleed
4. Chronic haemophilic arthropathy in both knees and the right elbow
5. Hepatitis C — treated with sustained virological response
6. Family history of severe haemophilia with a maternal uncle who died of intracranial haemorrhage ^[1]

"My immediate priorities are: first, to assess the headache — if there is any clinical suspicion of intracranial bleeding, I will give recombinant factor VIII immediately before imaging, because in severe haemophilia a headache is intracranial haemorrhage until proven otherwise. Second, to treat the knee haemarthrosis with factor VIII and rest. Third, to investigate why he has had a breakthrough bleed on emicizumab." ^[1]

Assessment of the headache — the critical decision: ^[1]

"The moderate headache is my greatest concern. In severe haemophilia, any new headache — even without a history of head injury — must be treated as potential intracranial haemorrhage until proven otherwise, because intracranial bleeding is the leading cause of death in haemophilia. The fact that his maternal uncle died of intracranial haemorrhage at 35 underscores the risk. My approach is: if there is any feature suggesting intracranial bleeding — decreased GCS, focal neurology, vomiting, seizure, or severe or worsening headache — I give recombinant factor VIII immediately to achieve a level of 80 to 100 IU/dL, and then arrange urgent CT head. I do NOT wait for imaging before giving factor, because the time to scan is time that bleeding continues. In this case, his GCS is 15 with no focal deficits and the headache is moderate rather than severe, so the risk is lower, but given his history I would have a low threshold for factor administration and imaging ^[1]."

Management plan: ^[1]

1. Assess the headache urgently. If concerned, give recombinant factor VIII 40-50 IU/kg IV immediately (to achieve 80-100 IU/dL — one unit per kilogram raises factor VIII by approximately 2 IU/dL), then arrange urgent CT head. If the CT is negative, the factor has done no harm; if it is positive, the factor has been life-saving. If the headache is clearly benign (mild, no red flags, improving), observe closely with neuro-observations every 2 hours. ^[1]

2. Treat the right knee haemarthrosis. Give recombinant factor VIII 20-25 IU/kg IV (to achieve approximately 40-50 IU/dL — adequate for a joint bleed). Rest the joint, apply ice, elevate. Analgesia: paracetamol-based — avoid NSAIDs and aspirin because they impair platelet function. If the bleed is severe or does not settle with one dose, repeat factor VIII at 12-hour intervals (factor VIII half-life is 12 hours). Do not aspirate the joint unless there is concern about septic arthritis — the risk of introducing infection and re-bleeding outweighs the benefit. ^[1]

3. Assess the thigh bruise. If it is a simple subcutaneous bruise, observe. If it is expanding or there is a tense, painful swelling suggesting an intramuscular bleed (especially in the iliopsoas or a compartment), escalate the factor dose to 80-100 IU/dL and consider imaging (ultrasound or MRI). ^[1]

4. Investigate the breakthrough bleed. A single breakthrough bleed on emicizumab does not mean the prophylaxis has failed — even the best prophylaxis allows occasional bleeds. But recurrent breakthroughs should prompt reassessment: check adherence to emicizumab injections, check that the dose is appropriate for his weight, and re-test for an inhibitor with a Bethesda assay. If an inhibitor has developed (rare on emicizumab but possible), the management strategy changes ^[2].

5. Long-term haemophilia management. Continue emicizumab prophylaxis. Discuss the full range of modern options: extended half-life factor VIII products (less frequent infusions), gene therapy (valoctocogene roxaparvovec — a single-dose AAV-based gene transfer that has shown sustained factor VIII expression for years in clinical trials). Refer to the comprehensive haemophilia treatment centre for ongoing multidisciplinary care ^[1].

Examiner discussion questions

Q: "Why does his aPTT remain prolonged even though he is on emicizumab?" ^[1]

"Emicizumab bridges factor IXa and factor X, effectively replacing the function of factor VIIIa — but it does not replace factor VIII itself. His factor VIII level remains less than 1 IU/dL because the underlying genetic deficiency is not corrected. The aPTT measures the intrinsic pathway, which includes factor VIII, so it remains prolonged. In fact, emicizumab can interfere with some aPTT-based assays — the aPTT may appear shorter than expected for a severe haemophilia patient because emicizumab accelerates the reaction in the test tube. The key point is that the aPTT is not useful for monitoring emicizumab — instead, the clinical bleeding rate is the measure of success ^[2]."

Q: "How would your management change if he had a high-titre factor VIII inhibitor?" ^[1]

"A factor VIII inhibitor would make standard factor VIII replacement ineffective — the antibody neutralises the infused factor. For acute bleeding in an inhibitor patient, I would use a bypassing agent: recombinant activated factor VII (rFVIIa) at 90 micrograms per kilogram every 2-3 hours, or activated prothrombin complex concentrate (FEIBA) at 50-100 IU/kg. If he were on emicizumab prophylaxis and developed an inhibitor, the emicizumab would largely solve the day-to-day problem — it works independently of factor VIII — but acute bleeds might still need a bypassing agent, or high-dose factor VIII if the inhibitor titre is low. Historically, immune tolerance induction — daily high-dose factor VIII for months — was used to eradicate the inhibitor, but emicizumab has largely reduced the need for this arduous approach ^[2]."

Q: "What are the long-term complications of severe haemophilia?" ^[1]

"First, chronic arthropathy from recurrent haemarthrosis — the synovium becomes chronically inflamed, the cartilage erodes, and the joint becomes deformed and painful. Daniel already shows signs of this in both knees and the right elbow. Joint replacement may eventually be needed. Second, blood-borne infection — historically HIV and hepatitis C from contaminated plasma-derived factor concentrates. Daniel contracted hepatitis C but achieved a cure with direct-acting antivirals. The modern recombinant factor products have eliminated this risk. Third, inhibitor development — 30 per cent of severe haemophilia A patients develop an inhibitor after factor exposure. Fourth, the psychosocial impact — chronic illness, pain, restrictions on activities, time off school and work, and anxiety about bleeding all take a toll ^[1]."

Q: "What is gene therapy for haemophilia and is Daniel a candidate?" ^[1]

"Gene therapy for haemophilia A uses an adeno-associated virus (AAV) vector to deliver a functional factor VIII gene to the liver, which then produces factor VIII endogenously. The pivotal trial of valoctocogene roxaparvovec showed sustained factor VIII expression after a single infusion, moving most patients from the severe into the mild range and dramatically reducing or eliminating bleeds. Daniel could be a candidate if he is 18 or older, has severe haemophilia A, has no pre-existing AAV antibodies (which would neutralise the viral vector), has no significant liver disease (the AAV must transduce hepatocytes), and understands that the factor VIII expression may decline over time and the long-term durability beyond 5-10 years is not yet known. He should be counselled that gene therapy does not cure the underlying genetic defect — he could still pass the haemophilia gene to his daughters — but it dramatically reduces or eliminates the bleeding phenotype ^[1]."

Q: "What advice would you give Daniel about sports and lifestyle?" ^[1]

"I would recommend safe physical activity. Swimming is excellent — it builds muscle strength that protects joints without impact loading, and it is already his preferred sport. I would encourage him to continue swimming and to maintain a healthy weight (obesity increases joint stress and bleeding risk). I would advise against contact sports (boxing, rugby, football) and high-impact activities that carry a risk of head injury or joint trauma. He should wear a medical alert bracelet. He should carry a letter from his haematology team detailing his condition and the emergency factor regimen. He should register with the haemophilia treatment centre for comprehensive annual review and have a clear plan for managing breakthrough bleeds. And he should inform his dentist and any surgeon of his condition before any procedure, so factor cover can be planned ^[1]."

Q: "If Daniel's future daughter is a carrier, what is the risk to her children?" ^[1]

"Haemophilia A is X-linked recessive. Daniel will pass his affected X chromosome to all of his daughters — they will all be obligate carriers. They will not have haemophilia themselves (they have a second X chromosome from their mother with a normal factor VIII gene), but each of their sons has a 50 per cent chance of having haemophilia A, and each of their daughters has a 50 per cent chance of being a carrier. Genetic counselling before pregnancy is essential — carrier testing and prenatal diagnosis are available, and preimplantation genetic diagnosis is an option. I would ensure Daniel and his partner have access to a clinical genetics service when they are considering starting a family ^[1]."